Maternal Milk, but Not Formula, Regulates the Immune Response to β-Lactoglobulin in Allergy-Prone Rat Pups

Tooley, Katie L.; El-Merhibi, Adaweyah; Cummins, Adrian G.; Grose, Randall H.; Lymn, Kerry A.; DeNichilo, Mark O.; Penttila, Irmeli A.

doi:10.3945/jn.109.108845

Cited by 13 publications

(21 citation statements)

References 43 publications

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“…Despite a recent report according to which commercially available pasteurized cow's milk may contain significant amounts (up to 1.5 ng/ml) of bovine TGF-␤ 2 which remains immunologically active in vitro and in vivo [22] , it is not known whether bovine TGF-␤ is present in infant formula. In experiments conducted using a rat model, it has been demonstrated that maternal milk protects rat pups from developing detrimental immune responses to orally administered bovine ␤ -lactoglobulin [23] . In line with this, feeding infant formula to rat pups results in an allergic-type immune response which is significantly reduced if the formula is supplemented with breast milk levels of TGF-␤ [24] .…”

Section: Discussionmentioning

confidence: 99%

Breast Milk-Transforming Growth Factor-β<sub>2</sub> Specifically Attenuates IL-1β-Induced Inflammatory Responses in the Immature Human Intestine via an SMAD6- and ERK-Dependent Mechanism

et al. 2010

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Background: Breast milk is known to protect the infant against infectious and immuno-inflammatory diseases, but the mechanisms of this protection are poorly understood. Objectives: We hypothesized that transforming growth factor-β₂ (TGF-β₂), an immunoregulatory cytokine abundant in breast milk, may have a direct anti-inflammatory effect on immature human intestinal epithelial cells (IECs). Methods: Human fetal ileal organ culture, primary human fetal IECs, and the human fetal small intestinal epithelial cell line H4 were stimulated with interleukin 1β (IL-1β) with or without TGF-β₂. Pro-inflammatory cytokine secretion and mRNA expression were measured by ELISA and quantitative real-time polymerase chain reaction, respectively. Alterations in ERK signalling were detected from IECs by immunoblotting and in fetal ileal tissue culture by immunohistochemistry. SMAD6 knockdown was performed by transfecting the cells with SMAD6 siRNA. Results: TGF-β₂ significantly attenuated IL-1β-induced pro-inflammatory cytokine production in fetal intestinal organ culture and the cell culture models. In addition, TGF-β₂ reduced the IL-1β-induced IL-8 and IL-6 mRNA response in H4 cells. TGF-β₂ markedly inhibited IL-1β-induced phosphorylation of ERK, which was necessary for the cytokine response. The inhibitory effect of TGF-β₂ on IL-1β-induced cytokine production was completely abrogated by SMAD6 siRNA knockdown. Conclusions: TGF-β₂ attenuates IL-1β-induced pro-inflammatory cytokine production in immature human IECs by inhibiting ERK signalling. The anti-inflammatory effect of TGF-β₂ is dependent on SMAD6. Breast milk TGF-β₂ may provide the neonate with important immunoregulatory support. TGF-β₂ might provide a novel means to improve intestinal immunophysiology in premature neonates.

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Section: Discussionmentioning

confidence: 99%

Breast Milk-Transforming Growth Factor-β<sub>2</sub> Specifically Attenuates IL-1β-Induced Inflammatory Responses in the Immature Human Intestine via an SMAD6- and ERK-Dependent Mechanism

et al. 2010

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“…FOXP3 TSDR demethylation was significantly lower in children with active IgE-mediated CMA than in either children who outgrew CMA or in healthy children [186]. Maternal rat milk in comparison with miRNA-deficient artificial formula increased mesenteric lymph node FoxP3 expression and decreased serum IgE levels to β-lactoglobulin in allergy-prone rat pups [197]. Thus, milk miRNAs operate like DNMT inhibitors that increase the stability of FOXP3 gene expression enhancing the suppressive capacity of Tregs, promoting an immune tolerance environment [198].…”

Section: Activation Of Developmental Genes Via Dna Cpg Demethylationmentioning

confidence: 99%

Milk’s Role as an Epigenetic Regulator in Health and Disease

2017

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Abstract:It is the intention of this review to characterize milk's role as an epigenetic regulator in health and disease. Based on translational research, we identify milk as a major epigenetic modulator of gene expression of the milk recipient. Milk is presented as an epigenetic "doping system" of mammalian development. Milk exosome-derived micro-ribonucleic acids (miRNAs) that target DNA methyltransferases are implicated to play the key role in the upregulation of developmental genes such as FTO, INS, and IGF1. In contrast to miRNA-deficient infant formula, breastfeeding via physiological miRNA transfer provides the appropriate signals for adequate epigenetic programming of the newborn infant. Whereas breastfeeding is restricted to the lactation period, continued consumption of cow's milk results in persistent epigenetic upregulation of genes critically involved in the development of diseases of civilization such as diabesity, neurodegeneration, and cancer. We hypothesize that the same miRNAs that epigenetically increase lactation, upregulate gene expression of the milk recipient via milk-derived miRNAs. It is of critical concern that persistent consumption of pasteurized cow's milk contaminates the human food chain with bovine miRNAs, that are identical to their human analogs. Commercial interest to enhance dairy lactation performance may further increase the epigenetic miRNA burden for the milk consumer.

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“…In an animal model, Strobel et al [14] have shown that oral OVA given in the first week of life to mice induces humoral as well as cell-mediated immunity [14]. In contrast, recent studies associate early antigen exposure with development of tolerance [15, 16]. More research is required to determine the optimum intervention strategy to promote oral tolerance.…”

Section: Introductionmentioning

confidence: 99%

“…Although the relationship between breastfeeding and allergy prevention is controversial [24–26], there has recently been a growing interest in the role of breast milk in regulating immune response development to food antigens as new foods are introduced into the diet [16, 27]. …”

Section: Introductionmentioning

confidence: 99%

“…The developing immune response was assessed when OVA was introduced into the diet during a critical time in early life. Formula-fed groups were included as controls, as we have previously shown sensitization after early oral antigen feeding in formula-fed pups [16]. Egg ovalbumin was used as the target antigen to assess antigen-specific responses as it is one of the most common causes of food allergy in infants.…”

Section: Introductionmentioning

confidence: 99%

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Early Oral Ovalbumin Exposure during Maternal Milk Feeding Prevents Spontaneous Allergic Sensitization in Allergy-Prone Rat Pups

El-Merhibi

Lymn

Kanter

et al. 2012

Clinical and Developmental Immunology

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There are conflicting data to support the practice of delaying the introduction of allergenic foods into the infant diet to prevent allergy development. This study investigated immune response development after early oral egg antigen (Ovalbumin; OVA) exposure in a rat pup model. Brown Norway (BN) rat pups were randomly allocated into groups: dam reared (DR), DR pups challenged daily (days 4–13) with oral OVA (DR + OVAc), DR pups challenged intermittently (on day 4, 10, 12, and 13) with oral OVA (DR + OVAi), formula-fed pups (FF), and FF pups challenged daily with oral OVA (FF + OVA). Immune parameters assessed included OVA-specific serum IgE, IgG1, and IgA. Ileal and splenic messenger ribonucleic acid (mRNA) expression of transforming growth factor-beta (TGF-β1), mothers against decapentaplegic (Smad) 2/4/7, and forkhead box P3 (Foxp3) were determined. Ileum was stained for TGF-β1 and Smad4. Results. Feeding OVA daily to DR pups maintained systemic and local gut antibody and immunoregulatory marker mRNA responses. Systemic TGF-β1 was lower in DR + OVAi pups compared to DR and DR + OVAc pups. Feeding OVA to FF pups resulted in significantly greater OVA-specific IgE and IgG1, and lower IgA and TGF-β1 and Smad expression compared to DR pups. Conclusions. Early daily OVA exposure in the presence of maternal milk maintains immune markers associated with a regulated immune response, preventing early allergic sensitization.

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Maternal Milk, but Not Formula, Regulates the Immune Response to β-Lactoglobulin in Allergy-Prone Rat Pups

Cited by 13 publications

References 43 publications

Breast Milk-Transforming Growth Factor-β<sub>2</sub> Specifically Attenuates IL-1β-Induced Inflammatory Responses in the Immature Human Intestine via an SMAD6- and ERK-Dependent Mechanism

Breast Milk-Transforming Growth Factor-β<sub>2</sub> Specifically Attenuates IL-1β-Induced Inflammatory Responses in the Immature Human Intestine via an SMAD6- and ERK-Dependent Mechanism

Milk’s Role as an Epigenetic Regulator in Health and Disease

Early Oral Ovalbumin Exposure during Maternal Milk Feeding Prevents Spontaneous Allergic Sensitization in Allergy-Prone Rat Pups

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